• Chia-Lung Tsai, Yun-Hsin Tang, Lan-Yan Yang, Angel Chao, Chin-Jung Wang, Chiao-Yun Lin, and Chyong-Huey Lai.
• Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
• J Formos Med Assoc. 2024 Oct 1; 123 (10): 104510561045-1056.

BackgroundImmune checkpoint inhibitors (ICIs) that against programmed cell death protein-1 (PD-1) and its ligand PD-L1 have been approved as a promising treatment of many human cancers. However, the responses to these ICIs were limited in patients with ovarian cancer. Studies have indicated that the response to PD-1/PD-L1 blockade might be correlated with the PD-L1 expression level in cancer cells. Nucleophosmin (NPM/B23) was found to be a potential target for immunotherapy. Whether NPM/B23 plays a role in cancer-associated immunity, such as PD-1/PD-L1 axis, and its underlying mechanisms remain largely unknown in ovarian cancer.MethodsWe applied ovarian cancer cell lines as research models. The effect of modulating PD-L1 by NPM/B23 was subsequently confirmed via Western blot, flow cytometry, qRT-PCR, luciferase reporter assays, and immunoprecipitation. Protein stability and ubiquitin assay assays were used to analyze the interplay between NPM/B23 and NF-ĸB/p65 in PD-L1 regulation. The MOSEC/Luc xenograft mouse model was used to validate the role of NPM/B23-PD-L1 through tumor growth in vivo.ResultsOur results revealed that NPM/B23 negatively regulates PD-L1 expression via a protein complex with NF-κB/p65 and through an IFN-γ pathway. Moreover, NPM/B23 inhibitor/modulator sensitized ovarian cancer cells to the anti-PD-1 antibody by regulating PD-L1 expression in the immunocompetent mouse model. Compared to anti-PD-1 antibody alone, a combination of anti-PD-1 antibody and NPM/B23 inhibitor/modulator showed reduced tumorigenesis and increased CD8+ T-cell expansion, thus contributing to prolonged survival on MOSEC/Luc-bearing mouse model.ConclusionTargeting NPM/B23 is a novel and potential therapeutic approach to sensitize ovarian cancer cells to immunotherapy.Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.

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